Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol

Sonia M S Espirito Santo, Nuno M M Pires, Lianne S M Boesten, Gery Gerritsen, Niels Bovenschen, Ko Willems Van Dijk, J. Wouter Jukema, Hans M G Princen, André Bensadoun, Wei Ping Li, Joachim Herz, Louis M. Havekes, Bart J M Van Vlijmen

Research output: Contribution to journalArticle

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Abstract

The low-density lipoprotein (LDL) receptor-related protein (LRP) has a well-established role in the hepatic removal of atherogenic apolipoprotein E (APOE)-rich remnant lipoproteins from plasma. In addition, LRP recognizes multiple distinct pro- and antiatherogenic ligands in vitro. Here, we investigated the role of hepatic LRP in atherogenesis independent of its role in removal of APOE-rich remnant lipoproteins. Mice that allow inducible inactivation of hepatic LRP were combined with LDL receptor and APOE double-deficient mice (MX1Cre+LRPflox/floxLDLR -/-APOE-/- On an LDLR-/-APOE-/- background, hepatic LRP deficiency resulted in decreased plasma cholesterol and triglycerides (cholesterol: 17.1 ± 5.2 vs 23.4 ± 6.3 mM, P = . 025; triglycerides: 1.1 ± 0.5 vs 2.2 ± 0.8 mM, P = .002, for MX1Cre+LRPflox/flox-LDLR-/-APOE-/- and control LRPflox/flox-LDLR-/-APOE-/- mice, respectively). Lower plasma cholesterol in MX1Cre+LRP flox/flox-LDLR-/-APOE-/- mice coincided with increased plasma lipoprotein lipase (71.2 ± 7.5 vs 19.1 ± 2.4 ng/ml, P = .002), coagulation factor VIII (4.4 ± 1.1 vs 1.9 ± 0.5 U/mL, P = .001), von Willebrand factor (2.8 ± 0.6 vs 1.4 ± 0.3 U/mL, P = .001), and tissue-type plasminogen activator (1.7 ± 0.7 vs 0.9 ± 0.5 ng/ml, P = .008) compared with controls. Strikingly, MX1Cre +-LRPflox/floxLDLR-/-APOE-/- mice showed a 2-fold higher atherosclerotic lesion area compared with controls (408. 5 ± 115.1 vs 219.1 ± 86.0 103μm2, P = .003). Our data indicate that hepatic LRP plays a clear protective role in atherogenesis independent of plasma cholesterol, possibly due to maintaining low levels of its proatherogenic ligands.

Original languageEnglish (US)
Pages (from-to)3777-3782
Number of pages6
JournalBlood
Volume103
Issue number10
DOIs
StatePublished - May 15 2004

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LDL-Receptor Related Proteins
Protein Deficiency
LDL Receptors
Apolipoproteins E
Low Density Lipoprotein Receptor-Related Protein-1
Atherosclerosis
Cholesterol
Plasmas
Liver
Proteins
Lipoproteins
Triglycerides
Ligands
Lipoprotein Lipase
Factor VIII
von Willebrand Factor
Tissue Plasminogen Activator

ASJC Scopus subject areas

  • Hematology

Cite this

Espirito Santo, S. M. S., Pires, N. M. M., Boesten, L. S. M., Gerritsen, G., Bovenschen, N., Van Dijk, K. W., ... Van Vlijmen, B. J. M. (2004). Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol. Blood, 103(10), 3777-3782. https://doi.org/10.1182/blood-2003-11-4051

Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol. / Espirito Santo, Sonia M S; Pires, Nuno M M; Boesten, Lianne S M; Gerritsen, Gery; Bovenschen, Niels; Van Dijk, Ko Willems; Jukema, J. Wouter; Princen, Hans M G; Bensadoun, André; Li, Wei Ping; Herz, Joachim; Havekes, Louis M.; Van Vlijmen, Bart J M.

In: Blood, Vol. 103, No. 10, 15.05.2004, p. 3777-3782.

Research output: Contribution to journalArticle

Espirito Santo, SMS, Pires, NMM, Boesten, LSM, Gerritsen, G, Bovenschen, N, Van Dijk, KW, Jukema, JW, Princen, HMG, Bensadoun, A, Li, WP, Herz, J, Havekes, LM & Van Vlijmen, BJM 2004, 'Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol', Blood, vol. 103, no. 10, pp. 3777-3782. https://doi.org/10.1182/blood-2003-11-4051
Espirito Santo SMS, Pires NMM, Boesten LSM, Gerritsen G, Bovenschen N, Van Dijk KW et al. Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol. Blood. 2004 May 15;103(10):3777-3782. https://doi.org/10.1182/blood-2003-11-4051
Espirito Santo, Sonia M S ; Pires, Nuno M M ; Boesten, Lianne S M ; Gerritsen, Gery ; Bovenschen, Niels ; Van Dijk, Ko Willems ; Jukema, J. Wouter ; Princen, Hans M G ; Bensadoun, André ; Li, Wei Ping ; Herz, Joachim ; Havekes, Louis M. ; Van Vlijmen, Bart J M. / Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol. In: Blood. 2004 ; Vol. 103, No. 10. pp. 3777-3782.
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abstract = "The low-density lipoprotein (LDL) receptor-related protein (LRP) has a well-established role in the hepatic removal of atherogenic apolipoprotein E (APOE)-rich remnant lipoproteins from plasma. In addition, LRP recognizes multiple distinct pro- and antiatherogenic ligands in vitro. Here, we investigated the role of hepatic LRP in atherogenesis independent of its role in removal of APOE-rich remnant lipoproteins. Mice that allow inducible inactivation of hepatic LRP were combined with LDL receptor and APOE double-deficient mice (MX1Cre+LRPflox/floxLDLR -/-APOE-/- On an LDLR-/-APOE-/- background, hepatic LRP deficiency resulted in decreased plasma cholesterol and triglycerides (cholesterol: 17.1 ± 5.2 vs 23.4 ± 6.3 mM, P = . 025; triglycerides: 1.1 ± 0.5 vs 2.2 ± 0.8 mM, P = .002, for MX1Cre+LRPflox/flox-LDLR-/-APOE-/- and control LRPflox/flox-LDLR-/-APOE-/- mice, respectively). Lower plasma cholesterol in MX1Cre+LRP flox/flox-LDLR-/-APOE-/- mice coincided with increased plasma lipoprotein lipase (71.2 ± 7.5 vs 19.1 ± 2.4 ng/ml, P = .002), coagulation factor VIII (4.4 ± 1.1 vs 1.9 ± 0.5 U/mL, P = .001), von Willebrand factor (2.8 ± 0.6 vs 1.4 ± 0.3 U/mL, P = .001), and tissue-type plasminogen activator (1.7 ± 0.7 vs 0.9 ± 0.5 ng/ml, P = .008) compared with controls. Strikingly, MX1Cre +-LRPflox/floxLDLR-/-APOE-/- mice showed a 2-fold higher atherosclerotic lesion area compared with controls (408. 5 ± 115.1 vs 219.1 ± 86.0 103μm2, P = .003). Our data indicate that hepatic LRP plays a clear protective role in atherogenesis independent of plasma cholesterol, possibly due to maintaining low levels of its proatherogenic ligands.",
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T1 - Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol

AU - Espirito Santo, Sonia M S

AU - Pires, Nuno M M

AU - Boesten, Lianne S M

AU - Gerritsen, Gery

AU - Bovenschen, Niels

AU - Van Dijk, Ko Willems

AU - Jukema, J. Wouter

AU - Princen, Hans M G

AU - Bensadoun, André

AU - Li, Wei Ping

AU - Herz, Joachim

AU - Havekes, Louis M.

AU - Van Vlijmen, Bart J M

PY - 2004/5/15

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N2 - The low-density lipoprotein (LDL) receptor-related protein (LRP) has a well-established role in the hepatic removal of atherogenic apolipoprotein E (APOE)-rich remnant lipoproteins from plasma. In addition, LRP recognizes multiple distinct pro- and antiatherogenic ligands in vitro. Here, we investigated the role of hepatic LRP in atherogenesis independent of its role in removal of APOE-rich remnant lipoproteins. Mice that allow inducible inactivation of hepatic LRP were combined with LDL receptor and APOE double-deficient mice (MX1Cre+LRPflox/floxLDLR -/-APOE-/- On an LDLR-/-APOE-/- background, hepatic LRP deficiency resulted in decreased plasma cholesterol and triglycerides (cholesterol: 17.1 ± 5.2 vs 23.4 ± 6.3 mM, P = . 025; triglycerides: 1.1 ± 0.5 vs 2.2 ± 0.8 mM, P = .002, for MX1Cre+LRPflox/flox-LDLR-/-APOE-/- and control LRPflox/flox-LDLR-/-APOE-/- mice, respectively). Lower plasma cholesterol in MX1Cre+LRP flox/flox-LDLR-/-APOE-/- mice coincided with increased plasma lipoprotein lipase (71.2 ± 7.5 vs 19.1 ± 2.4 ng/ml, P = .002), coagulation factor VIII (4.4 ± 1.1 vs 1.9 ± 0.5 U/mL, P = .001), von Willebrand factor (2.8 ± 0.6 vs 1.4 ± 0.3 U/mL, P = .001), and tissue-type plasminogen activator (1.7 ± 0.7 vs 0.9 ± 0.5 ng/ml, P = .008) compared with controls. Strikingly, MX1Cre +-LRPflox/floxLDLR-/-APOE-/- mice showed a 2-fold higher atherosclerotic lesion area compared with controls (408. 5 ± 115.1 vs 219.1 ± 86.0 103μm2, P = .003). Our data indicate that hepatic LRP plays a clear protective role in atherogenesis independent of plasma cholesterol, possibly due to maintaining low levels of its proatherogenic ligands.

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